CATIONIC RESIDUES IN PATHOGENIC ANTI-DNA AUTOANTIBODIES ARISE BY MUTATIONS OF A GERM-LINE GENE THAT BELONGS TO A LARGE VH GENE SUBFAMILY

The F1 progeny of autoimmune NZB and normal SWR mice uniformly develop severe and accelerated lupus nephritis. The (SWR x NZB)F1 mice produce an oligoclonally expanded population of nephritogenic anti-DNA autoantibodies that share a recurrent cross-reactive idiotype (Id564), use highly homologous V(H) genes and surprisingly have the C(H) region allotype of the normal SWR parent. From extensive library analyses, we isolated 15 SWR germ-line genes which are most closely related to the pathogenic autoantibody V(H)564 gene and which also belong to the NPb subfamily of J558 V(H) genes. We found that the pathogenic V(H) genes are probably somatic variants of a SWR germ-line VH gene, SW6-3, and they have several basic amino acid substitutions, in addition to those already present in the SW6-3 germ-line gene. Since these pathogenic autoantibodies are not detectable in the sera of the normal SWR mice despite the presence of the SW6-3 gene, strong selection and expansion of B cells expressing the SW6-3 V(H) gene is probably occurring in (SWR x NZB)F1 lupus-prone mice. We also isolated eight germ-line genes from the NZB mouse which are homologous to SW6-3. The autoimmune NZB parent that rarely develops nephritis lacks the SW6-3 gene, but has several highly homologous germ-line V(H) genes that would encode less cationic antibodies. These results establish a correlation between structure and pathogenic potential of V(H) genes.